Mycobacterium tuberculosis kills 3 million each year, making it the single most deadly of all infectious diseases. In addition, resistance has developed to each of the current front-line TB therapies and a new antitubercular agent has not been developed in over thirty years. These facts underscore the need for new antitubercular compounds. However, TB is among the most difficult of organisms to study because of its slow doubling time and requirements for BL-3 containment. For this reason, some small molecule leads have not been adequately pursued despite their promise. To address this problem, new tools for rapid synthesis of diverse chemical libraries and mycobacterial drug susceptibility testing have been developed. With these new capabilities, compound series can be explored much more thoroughly, suggesting that a reevaluation of old leads is warranted. Five compound series have been chosen for investigation: isoniazid, Thiocarlide, phenothiazine, amidrazones and carbamoyl 5-hydroxypyrazoles. Those most amenable to automated matric chemistry, with the best potential to generate diverse libraries of novel compounds, will be advances to full-scale library synthesis and screening during Phase II of this proposal. PROPOSED COMMERCIAL APPLICATION The goal of this research is to create new drugs to combat tuberculosis and other mycobacterial infections. Since the need for new antimycobacterial therapies is great, the likelihood that this work will be commercialized is significant.